Exposure-Biomarkers Research Core
Research Accomplishments - 2006
During 2006, the Exposure-Biomarkers Research Core (EBRC) sponsored one Center-wide seminar by Dr. Radim Sram (Czech Inst Exptl Med).
Two core members, Profs. Rappaport and Chen were awarded CEHS pilot projects for 2005-06. Prof. Rappaport’s project, entitled “Measuring protein adducts in dried blood spots,” is intended to develop an assay for protein adducts of environmental toxicants in dried blood spots (DBS). Because DBS are considerably simpler to obtain and store than venous blood samples and are routinely collected from live births throughout the U.S., the ability to measure protein adducts in DBS would generate opportunities for molecular epidemiology studies. While the ultimate goal of this work will be to measure protein adducts from different environmental toxicants, in this pilot project the investigators seek proof of concept by focusing upon hemoglobin and albumin adducts of 1,4-benzoquinone (1,4-BQ), a metabolite thought to play a role in the leukemogenicity and hematotoxicity of benzene. Prof. Chen’s project, entitled “Health Effects of Air Pollution on Lupus (HEAPL): A Nested Pilot Study in a Community-Based Panel of Lupus Patients and Controls”, is being conducted in collaboration with Prof. Christakos. They will use spatiotemporal data to construct Bayesian Maximum Entropy (BME) models and estimate personal exposures to ambient PM10, PM2.5, and ozone for 265 patients with systemic lupus erythematosus (SLE) and 302 community-based controls from the Carolina Lupus Study. Among SLE patients, clinical markers of disease severity and activity will be examined for their associations with exposures to air pollution. To date, the research team has developed and validated the BME models suitable for the spatiotemporal interpolation of ambient air pollutants for this pilot study. They have been expanding the BME exposure estimate database and will soon begin the statistical analyses on individual susceptibility and health effects. This pilot study will generate preliminary but essential data to evaluate the susceptibility of SLE patients and the potential effects of air pollution on rheumatoid disorders.
Prof. Nylander-French, who received funds for a 2001 pilot project entitled “Dermal exposure to 1,6-hexamethylene diisocyanate in spray painting operations”, used the results of her pilot project in a successful grant applications to NIOSH and the American Chemistry Council. This work is being conducted in collaboration with Prof. Ball (described below under Interactions and Collaborations). The Biomarkers Facility Core assisted Prof. Nylander-French in developing the analytical methods for this project. During 2006, two manuscripts were been published from this work (Fent et al., Scand J Work Environ Health 32(3):225-240, 2006; Flynn et al., J Occup Environ Hyg 3:475–480, 2006). Her group has also conducted investigations of dermal exposure to JP-8 both in controlled human experiments and in an observational study of Air Force personnel (the latter in collaboration with Profs. Rappaport and Kupper, described below under Interactions and Collaborations).
Prof. Nylander-French (PI) submitted two R01 grant proposals to NIH (Biomarkers and Individual Differences in Response to Diisocyanate Exposure; Agricultural Exposure to Triazoles and Organophosphate Pesticides), in which collaboration with Profs. Herring (BEMFC Director since July 2006) and Zou (BEMFC, GSRC) is essential and provides the framework for the hypothesis testing.
Prof. Richardson received funding from NIOSH (K01-OH008635) to work on the application of mechanistic models in occupational cancer epidemiology. He also received a fellowship from the Alfried Krupp Kolleg Greifswald Foundation and Alfried Krupp von Bohlen und Halbach Foundation for the development of methods to study critical periods of environmental exposure in relation to onset of leukemias and lymphomas in the context of the Northern Germany Leukemia and Lymphoma study.
Prof. Schroeder used results of her 2002 CEHS pilot project to support a successful R21/R33 grant application to develop and optimize a novel set of PCR and in situ assays to detect EBV in archival lymphoma samples (1R21CA107966 “Epidemiology of Atypical Epstein-Barr Virus in Lymphoma” in collaboration with Dr. M. Gulley, UNC-CH Pathology and Laboratory Medicine). The R33 phase of this research will evaluate risk factors for typical and atypical EBV positive lymphomas in the Factors Affecting Rural Men (FARM) study (NCI, A. Blair). As a Director of the North Carolina Epidemiology Core, Prof. Schroeder has overseen enrollment and data collection from over 650 participants in the DoD funded PCaP study (PC21005: Schroeder et al., Prostate 66:1162-1176, 2006). In addition, Dr. Schroeder is PI of several ongoing PCaP ancillary studies, including the PCaP-GIS study of race, pesticides and prostate cancer aggressiveness in North Carolina men.
Profs. Serre and Christakos have continued to apply Bayesian Maximum Entropy techniques to construct spatiotemporal maps of man-made and natural pollutants and the progression of diseases. They recently coauthored a book, which compares spatiotemporal maps of the Black Death in the 14th century with those from known outbreaks of the bubonic plague. Their analyses strongly suggest that the Black Death was not caused by the bacterium responsible for the bubonic plague (described below under Interactions and Collaborations). Prof. Serre is applying the concepts developed in the spatiotemporal modeling of infectious diseases in collaboration with Prof. Miller (Epidemiology, UNC-CH). Other important applications include the spatiotemporal water quality assessment along rivers, a work that is now being expanded to integrate data obtained from fish tissue samples, and spatiotemporal modeling of air pollutants, which is used in collaboration of various epidemiological projects looking at the association between ammonia, hydrogen sulfide, particulate matter, and corresponding markers of health effects.
Interactions and Collaborations
Profs. Nylander-French and Ball are investigating the dermal uptake and metabolism of 1,6-hexamethylene diisocyanate. This work was motivated by a pilot project in the first year of the TSRC and led to funded research projects by NIOSH (R01 OH007598, Nylander-French PI, Dermal Exposure to 1,6-Hexamethylene Diisocyanate) and the American Chemistry Council (Nylander-French PI, Biomarkers of Exposure to Hexamethylene Diisocyanate). The purpose of these projects is to develop and apply methods for measurement of 1,6-hexamethylene diisocyanate (HDI) exposure of spray painters who are at risk for sensitization and development of occupational asthma and to investigate the relative importance of dermal and inhalation exposure in developing a systemic response. Diisocyanates are powerful skin sensitizers and a leading cause of occupationally induced asthma. Profs. Nylander-French and Ball are investigating the relative importance of dermal and inhalation exposure in developing a systemic response to HDI (i.e., HDI metabolite 1,6-hexamethylene diamine in urine and blood and HDI-adducted keratin in the skin). An enzyme-linked immunosorbent assay (ELISA) method for detection of HDI-adducted keratin has been developed to measure HDI absorption and the potential systemic bioavailability via the skin. During 2006, two manuscripts were published from this work (Fent et al., Scand J Work Environ Health 32(3):225-240, 2006; Flynn et at., J Occup Environ Hyg 3:475–480, 2006).
Profs. Nylander-French, Rappaport, and Kupper (BEMFC Director and EBRC member) have investigated naphthalene and its biomarkers as measures of dermal and inhalation exposure to jet fuel (JP-8). This study was conducted with funding from NIEHS (through the Superfund Basic Research Program) and with a contract from the U. S. Air Force. This work led to a joint publication (Chao et al., Environ Health Perspect 114(2):182-185, 2006; Kim et al., Environ Health Perspect , submitted). The work suggests that naphthalene and its metabolites will serve as useful measures of exposure to jet fuel by both dermal absorption and inhalation. Also, as a result of this collaboration, a statistical paper on the use of predictor variable importance methods when modeling environmental data is being prepared for submission to Environmental Health Perspectives (Chao et al., manuscript).
Prof. Nylander-French (PI) has collaborated with Profs. Herring (BEMFC Director since July 2006) and Zou (BEMFC, GSRC) on two grant proposals submitted to NIH, which benefited from the interactions facilitated by the CEHS.
Profs. Rappaport, Nylander-French, and Kupper collaborated on a study designed to determine important predictors of occupational exposure to styrene and styrene-7,8-oxide in the reinforced plastics industry. One manuscript emanating from this collaboration has been published (Serdar et al., Occup Environ Med 63(10):707-712, 2006).
Profs. Rappaport and Kupper in collaboration with Dr. Taylor (BEMFC affiliate) and Prof. Johnson (a former postdoctoral trainee on Prof. Kupper’s Environmental Biostatistics training grant funded by NIEHS and currently an Assistant Professor in the Dept. of Biostatistics at Emory University) are developing hybrid statistical/toxicokinetic models to the analysis of exposure-biomarker relationships as part of a funded by the American Chemistry Council (Rappaport PI, Statistical Methods for Evaluating Exposure-Biomarker Relationships). The purpose of the project is to incorporate information gleaned from studies of human exposure and biomarkers about the uptake, bioactivation, and detoxification of toxic chemicals into human risk assessments. Valid and precise quantification of exposure-biomarkers relationships has been hampered by at least three problems: (1) large variability in observed exposure and biomarker levels both within and between subjects; (2) errors in the measurement of both exposure and biomarker levels; and, (3) exposure and biomarker levels that fall below known detection limits. This research involves the use of non-linear mixed models, toxicokinetic theory, and measurement error methods to model exposure-biomarker regression relationships, taking into account measurement error in both exposure and biomarker levels as well as the effects of between-person and within-person variability. The investigators apply maximum likelihood methods that appropriately adjust for these problems and that are applicable for biomarkers that are either short-term or long-term in nature. This project has led to three publications thus far (Rappaport et al., Toxicol Sci, 83:224-236, 2005; Johnson et al., J Ag Bio Environ Stat, 10(4):440-459, 2005; Lin et al., Occup Environ Med, 62:750-760, 2005) and one manuscript is currently under review with the journal Biometrics.
Profs. Serre and Christakos have developed the conceptual and numerical framework for the Bayesian Maximum Entropy (BME) estimation method for space-time mapping using various types of physical knowledge. This work has been supported by our NIEHS Superfund Basic Research Program and by a grant from the U S Army Research Office. During the last year interesting applications of BME have been published regarding the Chernobyl fallouts (Savelieva et al., Geoderma, in press) and the Black Death pandemic of the 14th century (Christakos et al., Interdisciplinary Public Health Reasoning and Epidemic Modelling: The Case of Black Death, 2005, Springer). The study of the Black Death starts by focusing on the intellectual context in which epidemic research takes place, in a way that accounts for the interdisciplinary and multicultural trends of the emerging Conceptual Age. The investigators apply a variety of approaches to develop, for the first time, a series of detailed space-time maps of Black Death mortality, infected area propagation, and epidemic centroid paths throughout the 14th century AD Europe. Preparation of the maps took into account the uncertain nature of the data and integrated a variety of interdisciplinary knowledge bases about the devastating epidemic. This book carefully analyzes the findings of synthetic space-time modeling that enlighten considerably the long-lasting controversy about the nature and origins of the Black Death pandemic. Comparisons are made between the spatiotemporal characteristics of Black Death and bubonic plague, thus contributing to the debate concerning the Black Death etiology. Since Black Death had grave societal, public health, and financial effects, its rigorous study can offer valuable insight into these effects, as well as into similar effects that could result from potential contemporary epidemics.
Profs. Chen and Christakos are collaborating in a CEHS pilot project, entitled “Health Effects of Air Pollution on Lupus (HEAPL): A Nested Pilot Study in a Community-Based Panel of Lupus Patients and Controls”. They are using spatiotemporal data to construct Bayesian Maximum Entropy (BME) models and estimate personal exposures to PM10, PM2.5, and ozone for 265 patients with systemic lupus erytheomatosus (SLE) and 302 community-based controls from the Carolina Lupus Study. Within the BME framework proposed for and the funding from this CEHS pilot project, Profs. Chen and Christakos have supervised one post-doctoral trainee to develop a new analytical approach to spatio-temporal modeling (Yu et al., Med Geography, in press).
Profs. Chen and Serre are working together to study the obesity-related environmental health susceptibility. They collaborate with Prof. Herring and Dr. Joanne Jordan (Rheumatology, Allergy and Immunology) in developing a project to study the obesity-related susceptibility to vascular inflammatory responses to air pollution. Profs. Chen and Serre are also collaborating with Prof. Crawford-Brown of the Carolina Environmental Program in developing a project tentatively titled “Indicators of Environmental Health for Community-Based Assessments” in response to the EPA-STAR RFP (EPA-G2007-STAR-A1). Prof. Chen has also collaborated with Dr. Daniel Pomp (UNC Dept. Nutrition; Cell and Molecular Physiology) in the subject of obesity-related susceptibility to adverse health effects of ambient air pollution. With the unique polygenic obese mouse (the M16 line) developed by Dr. Pomp, Prof. Chen recently succeeded in bridging the collaboration between Dr. Pomp and EPA inhalation toxicologists Drs. Costa and Gavett to launch a pilot study to define the phenotypic and genomic characterization of obesity-associated susceptibility to PM health effects. Prof. Chen instilled his interdisciplinary research experience and EHS perspectives into his collaboration with Dr. Jordan and other faculty and scientists at the UNC Thurston Arthritis Research Center. In the recent P50 project (PI: Jordan) in response to NIEHS DISCOVER Center RFA, he helped establish the conceptual framework for proposed environmental rheumatology, integrate basic science (toxicogenomics, animal models, in vitro toxicological experiments) and population-based studies around the inter-related research theme, and provide the EHS context to use metal toxicants as an environmental probe for studying the pathogenesis and progression of osteoarthritis and associated clinical outcomes.
Prof. Gammon collaborated with Profs. Olshan and Schroeder (Gaudet et al., Breast Cancer Res Treat 99(2):235-40, 2006) and with Profs. Millikan and Schroeder (Fink et al., Am J Epid, on line Dec 11, 2006) on several applications in the “Long Island Breast Cancer Study Project."
Prof. Richardson has collaborated with Profs. Wing and Schroeder in a study of radiation induced cancers (Richardson et al., Environ Health Perspect, 113:1-5, 2005; Wing et al., Occup Environ Med 62:465-472, 2005). Prof. Richardson recently submitted a grant application to NIOSH, entitled, “Cohort analysis methods for occupational cancer studies” which includes Prof. Chen as co-investigator. The objective of this study is to improve the analytic tools available to address three common methodological issues (latency effect; measurement errors in aggregated exposure data; healthy worker survivor effects) commonly encountered in studying cancer mortality associated with protracted low levels of occupational exposures.
Profs. Richardson and Wing have collaborated in a study of exposures in a uranium enrichment facility and lung cancer (Richardson et al., AJIM 49:102-111, 2006), and in a study of radiation exposure and cancer at a plutonium production facility (Richardson et al., J Exp Sci Environ Epid, on line June 28, 2006).
Prof. Schroeder collaborated with Profs. Gammon and Olshan on analyses of the Long Island Breast Cancer Study (Fink et al., Am J Epid, on line Dec 11, 2006; Gaudet et al., Breast Cancer Res Treat, 99:235-40, 2006). She has also collaborated with Profs. Millikan and Sandler in an ongoing cohort study of colon cancer among African Americans (Sansbury et al., Cancer Causes Control 17:257-66, 2006; Huang et al., Cancer Causes Control 17:385-394, 2006).
Prof. Loomis has two joint publications with Profs. Olshan and Herring in which they describe new methods for analyzing epidemiological data (Gilboa et al., Environ Res 101(2):256-62, 2006; Gilboa et al., Birth Defects Res A Clin Mol Teratol 76(1):60-5, 2006. Prof. Loomis also collaborated with Prof. Nylander-French in a study of commercial fishers exposure to fuel emissions (Kirrane et al., J Expo Sci Environ Epidemiol, on line May 31, 2006).
Prof. Swenberg’s major research focus is developing and applying new biomarker methods for DNA and protein adducts of occupational and environmental chemicals. During the past year, his laboratory has greatly improved the methods for the adducts formed by reactive intermediates of butadiene (BD) and applied these methods to tissue samples from rats and mice exposed to 1 – 625 ppm BD for 2 or 4 weeks. They have been able to measure DNA-DNA cross-links for the first time, as well as N-7 guanine adducts. These are being compared with hprt mutations. In collaboration with The Biomarker Facility Core, major improvements in sensitivity (50-fold) have been achieved in the pyr-Val assay for BD diepoxide globin adducts in mice, rats and humans. Several methods for biomarkers of oxidative DNA damage also have been improved and are being used to investigate the role of ROS in PAH and PCB exposed rats and fish, including fish from the Hudson River Superfund site. Prof. Swenberg has initiated new biomarker studies on formaldehyde DNA-DNA cross-links, N6-OHmethyldA and DNA-protein cross-links in collaboration with Dr. Steve Hecht (University of Minnesota). These biomarkers are being evaluated in rat nasal epithelium, as well as distant sites in animals exposed by inhalation to 10 ppm [13CD2]-formaldehyde for 1 or 5 day so that endogenous adducts can be differentiated from those caused by inhalation exposure.
Profs. Swenberg (PI, CEHS Director and EBRC member) and Kupper (BEMFC Director and EBRC member) are collaborating on a NIEHS-funded research project entitled “Adducts as Quantitative Markers of Butadiene Mutagenesis” (RO1 ES012689) to identify critical metabolites and DNA adducts involved in butadiene-induced mutagenesis and carcinogenesis by comparing the molecular dose of previously unexplored DNA adducts with the induction of mutations and changes in expression. This research also involves collaboration with Drs. Vernon Walker (a member of the New Mexico Environmental Health Center), Jonathon Ward (UT-Galveston Center for Environmental Health), and Natalia Tretyakova (University of Minnesota).
Profs. Swenberg and Ball coauthored two publications on mass spectrometry methods (Li et al., Rapid Commun Mass Spectrom 20(2):185-92, 2006; Stout et al., Chem Res Toxicol 19(4):563-70, 2006).
